This proposal will utilize a particularly favorable axon preparation, the crayfish medial giant axon, to seek improved experimental resolution concerning a carefully chosen selection of key questions with respect to the physiological mechanisms of membrane excitability. Among the questions posed are: a) are the separate components of gating current generated by semi-independent particles of differing valence? b) are any of these gating current components directly generated by the opening and/or closing of channel gates? c) can kinetic components be similarly identified within sodium current transients? d) are fast and slow inactivation separate and parallel processes or are they integral components of a sequential conductance control system? e) can the kinetic components of sodium current be related to specific kinetic components of gating current? Answers will be sought through sophisticated kinetic analysis in addition to using pharmacological agents to modify normal axon behavior. Results will be used to generate a biophysically rigorous physiological model which can then be used to predict additional, experimentally testable, aspects of axon excitability. The health related aspects of this line of research may add to the understanding of neural excitability in man and help in designing new or safer local anesthetic and anti-arrythmic drugs. Results of this work will increase our basic understanding of other systems including: autonomic, central, peripheral and cardiovascular systems since these systems have similar basic mechanisms of ion conductance control.